Abstract My vision for the new innovator application is to address the antibiotic resistance crisis by identifying synergistic combinations of natural products from soil bacteria. Living in highly competitive environments, soil bacteria have not only evolved highly potent antibiotics for self defense and survival, but also combinations of compounds to overcome intrinsic antibiotic resistance in their microbial competitors. One such natural combination of ?-lactam antibiotic and anti-resistance compound clavulanic acid has been developed as one of the most widely used antibiotic cocktails, AugmentinTM. Antimicrobial combination therapy like Augmentin is powerfulbutdifficulttodiscoveranddevelopviatraditionalmethods.Myuniqueapproachisto integrate tools of bioinformatic prediction, microbial signaling, and natural product chemistry to identify novel and effective antibiotic cocktails that bacteria have already evolved, by taking advantage of the rapidly growing bacterial genome information. We have already obtained preliminaryresultsthatstronglysupportourvision.Thisprojectwillbecarriedoutintwostages: first, we will develop novel genome-mining approaches to identify combinations of natural products that are co-expressed under stress and likely have synergistic functions. Second, we will characterize the chemical structures and synergistic mechanisms of the cocktails we identify, focusing on combinations that exhibit the highest potency against multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Our proposed studies will provide fundamental insights for how to design synergistic antibiotics and avoid acquired resistance, addresstheurgentneedforinnovationinantimicrobialtherapyagainstdrug-resistantinfections, andreapthebenefitsofantibioticsfrommicrobesforagestocome.